Mortality in infants with cardiovascular malformations.

UNLABELLED: Cardiovascular malformations are an important cause of infant death and the major cause of death due to malformation. Our aims were to analyse and categorise all deaths in infants with cardiovascular malformations, and to analyse trends in mortality over time and influences on mortality. We obtained details of infant deaths and cardiovascular malformations from the population of one health region for 1987-2006. We categorised deaths by cause and by presence of additional chromosomal or genetic abnormalities or non-cardiac malformations. In 676,927 live births the total infant mortality was 4,402 (6.5 per 1,000). A total of 4,437 infants had cardiovascular malformations (6.6 per 1000) of whom 458 (10.3%) died before 1 year of age. Of this number, 151 (33%) deaths had non-cardiac causes, 128 (28%) were cardiac without surgery and 179 (39%) occurred from cardiac causes after surgery. Death was unrelated to the cardiovascular malformation in 57% of infants with an additional chromosomal or genetic abnormality, in 76% of infants with a major non-cardiac malformation and in 16% of infants with an isolated cardiovascular malformation. Terminations of pregnancies affected by cardiovascular malformations increased from 20 per 100,000 registered births in the first 5 years to 78 per 100,000 in the last 5 years. A total of 2,067 infants (47%) underwent surgery and of these 216 (10%) died before 1 year of age. CONCLUSIONS: A total of 10.4% of infants who died had a cardiovascular malformation and two-thirds of deaths were due to the malformation or its treatment. Mortality declined due to increasing termination of pregnancy and improved survival after operation.

Scanning laser-induced endothelial injury: a standardized and reproducible thrombosis model for intravital microscopy.

Vascular injury models are indispensable for studying thrombotic processes in vivo. Amongst the available methods for inducing thrombosis, laser-induced endothelial injury (LIEI) has several unique advantages. However, a lack of methodological standardization and expensive instrumentation remain significant problems decreasing reproducibility and impeding the adoption of LIEI in the wider scientific community. In this, study, we developed a standardized protocol for scanning laser-induced endothelial injury (scanning-LIEI) of murine mesenteric veins using the intrinsic 405 nm laser of a conventional laser scanning confocal microscope. We show that our model produces thrombi with prominent core-shell architectures and minimal radiation-related fluorescence artefacts. In comparison with previous methods, the scanning-LIEI model exhibits reduced experimental variability, enabling the demonstration of dose-response effects for anti-thrombotic drugs using small animal cohorts. Scanning-LIEI using the intrinsic 405 nm laser of a confocal laser scanning microscope represents a new method to induce standardized vascular injury with improved reproducibility of thrombus formation. The reduced need for instrument customisation and user experience means that this model could be more readily adopted in the research community.

Multicenter experience of ABO-incompatible pediatric cardiac transplantation.

Although ABO blood group incompatible cardiac transplantation in neonates and infants reduces waiting list mortality without compromising outcome, the technique has not been adopted by all centers, and to date Toronto remains the only center to have published results from a large case series. We present a review of ABO-incompatible heart transplantation in the United Kingdom (UK) where current recipient selection criteria differ somewhat from those used in the United States (US) and Canada. Between February 2000 and November 2006, 21 ABO-incompatible cardiac transplants were performed in children aged 2-40 months (median 10.0). Immunosuppression followed standard regimens. Pretransplant donor-specific isohemagglutinins of >1:4, (the UNOS cutoff), were present in five patients and reduced by plasma exchange. After transplantation, 19/21 recipients demonstrated persisting deficiency of donor-specific isohemagglutinins. Significant donor-specific isohemagglutinins levels were detected repeatedly in 2/21 recipients who have shown no clinical or biopsy evidence of rejection. All recipients survive without retransplantation and there have been no episodes of humoral rejection. We conclude it is possible for other centers to replicate the excellent results achieved in Toronto and that ABO-incompatible transplantation may be performed successfully in some patients beyond infancy with established isohemagglutinin production providing preoperative antibody removing strategies are used.

Clinical experience with assisted venous drainage cardiopulmonary bypass in elective cardiac reoperations.

Reoperative cardiac surgery is associated with substantial morbidity and mortality due to technical problems at sternal reentry, which can result in laceration of the right ventricle, innominate vein injury, or embolization from patent grafts. To minimize the risk associated with reentry, we adopted the method of assisted venous drainage in the cardiopulmonary bypass circuit with peripheral cannulation for cardiac reoperations. From March 1999 to May 2003, a series of 52 patients (38 males; mean age 48.7 years, range 4 months to 78 years) underwent cardiac reoperations performed with centrifugal pump venous-assisted cardiopulmonary bypass. EuroSCORE was 7.34 +/- 3.9 (range, 4-19). The reoperations were coronary artery bypass graft (25 patients), valve replacement/repair (18 patients), and complex pediatric procedures (11 patients). The studied adverse events were structural damage at reentry, mortality, blood loss, stroke, and hemolysis. Complications at sternotomy were damage to the innominate vein (1 patient) and aorta (1 patient) with blood loss of 625 and 225 mL, respectively. Four patients required intraaortic balloon pump or extracorporeal membrane oxygenation (n = 1) for hemodynamic support on weaning off cardiopulmonary bypass. Three patients died in the postoperative period. Our experience with centrifugal pump-assisted venous drainage in cardiac reoperations has shown excellent results, with reduced risk of damage to vital structures on sternal reentry. In cases in which structural damage did occur, blood loss was minimal.

Transmissible gastroenteritis. Mechanisms responsible for diarrhea in an acute viral enteritis in piglets.

We studied 3-wk-old piglets 40 h after experimental infection with transmissible gastroenteritis (TGE) virus to identify the mechanisms of diarrhea in this disease and to better understand infectious diarrhea in humans. Using continuous segmental marker perfusion in four regions along the gut, we found significant increases in net intraluminal accumulation of water and electrolytes only in the proximal jejunum, the region infected by the virus. In this jejunal segment studied in vivo, unidirectional sodium flux, extracellular fluid (ECF) to lumen, significantly increased, lumen to ECF significantly decreased, compared with matchfed littermates. The standard perfusate rendered hypertonic by adding mannitol (450 mosmol/kg), in the same segment of normal pigs, caused only an increase in ECF to lumen flux of sodium. TGE did not alter gross villous structure or intraluminal bacteria, bile salts, lactate, pH, or osmolality. Epithelial cell migration was accelerated in the jejunum of infected pigs. Isolated in suspension, these cells from TGE pigs exhibited increased active and passive sodium efflux, cells from mannitol-perfused pigs exhibited only increased active sodium efflux. In this viral enteritis, altered sodium transport occurring in the jejunum, the region of the intestine infected appears to be associated with defective epithelial cell function. The precise nature of the abnormalities in sodium transport, their relationship to disturbances of transport of other solutes, and to virus epithelial cell interaction remain to be defined.

Human rotavirus enteritis induced in conventional piglets. Intestinal structure and transport.

To better understand the pathogenesis of infantile viral gastroenteritis, we studied Na+ and Cl- fluxes in vitro in short-circuited jejunal epithelium from 8-10-day-old piglets after infection with a standard dose of human rotavirus given via nasogastric tube. 11 infected piglets, all of whom became ill, were compared with 9 uninfected, healthy litter-mates. When killed 72 h after infection, intestinal villi were shorter and crypts deeper (P less than 0.025) in duodenum, upper jejunum, and mid-small intestine, but not ileum in infected piglets. Virus antigen was seen by fluorescence microscopy in occasional jejunal villus tip cells in only four infected piglets and no controls at 72 h. Net Na+ and Cl- fluxes did not differ from noninfected litter-mate controls under basal conditions, but response to glucose was blunted in infected piglets (P less than 0.001). Theophylline stimulated net Cl- secretion in both infected and control animals, and cyclic AMP concentration in isolated jejunal villus enterocytes did not differ significantly. In isolated jejunal villus enterocytes of infected piglets, thymidine kinase activity increased (P less than 0.001), and sucrase activity decreased (P less than 0.001). We conclude that in this invasive enteritis caused by a major human viral pathogen, glucose-coupled Na+ transport is impaired in the jejunum at a time when the villus epithelium shows enzyme characteristics of crypt epithelium, and when little or no virus is present. These findings are identical to those occurring in an invasive coronavirus enteritis of piglets but differ markedly from those seen with enterotoxigenic diarrhea.

Increased expression of protease-activated receptor-2 (PAR2) and PAR4 in human coronary artery by inflammatory stimuli unveils endothelium-dependent relaxations to PAR2 and PAR4 agonists.

Protease-activated receptor (PAR)1 and PAR2 are expressed on vascular endothelial cells and mediate endothelium-dependent relaxation in several species, and PAR4 agonists cause similar responses in rat aortas. To date, only PAR1 has been reported to mediate relaxation of human arteries despite endothelial cell expression of both PAR1 and PAR2 in these tissues. Because inflammatory stimuli increase PAR2 expression in human endothelial cells in culture, the present study investigated the effect of similar stimuli on PARs in human isolated coronary arteries (HCAs). In HCA ring segments suspended for isometric tension measurements, the selective PAR1-activating peptide, TFLLR (0.01 to 10 micromol/L), caused endothelium-dependent relaxation of precontracted preparations. Little or no change in vascular tension was elicited by either the PAR2- or PAR4-activating peptides, SLIGKV and GYPGQV, respectively (up to 100 micromol/L). Exposure of HCAs to interleukin (IL)-1alpha (1 ng/mL, 12 hours) or tumor necrosis factor-alpha (3 nmol/L, 12 hours) did not affect PAR1 expression but increased PAR2 and PAR4 mRNA levels by approximately 5- and 4-fold, respectively, as determined by quantitative polymerase chain reaction. Similar IL-1alpha treatment did not affect TFLLR-induced relaxations but revealed significant endothelium-dependent relaxations to SLIGKV (100 micromol/L, 61.4+/-6.7%) and GYPGQV (100 micromol/L, 34.8+/-6.4%). These studies are the first to demonstrate functional PAR2 and PAR4 in human arteries in situ. The selective upregulation of PAR2 and PAR4 expression and the increased vascular response in HCAs after exposure to inflammatory stimuli suggest a role for these endothelial receptors during inflammation.

Inhibition of protease-activated receptor 4 impairs platelet procoagulant activity during thrombus formation in human blood.

UNLABELLED: Essentials The platelet thrombin receptor, PAR4, is an emerging anti-thrombotic drug target. We examined the anti-platelet & anti-thrombotic effects of PAR4 inhibition in human blood. PAR4 inhibition impaired platelet procoagulant activity in isolated cells and during thrombosis. Our study shows PAR4 is required for platelet procoagulant function & thrombosis in human blood. SUMMARY: Background Thrombin-induced platelet activation is important for arterial thrombosis. Thrombin activates human platelets predominantly via protease-activated receptor (PAR)1 and PAR4. PAR1 has higher affinity for thrombin, and the first PAR1 antagonist, vorapaxar, was recently approved for use as an antiplatelet agent. However, vorapaxar is contraindicated in a significant number of patients, owing to adverse bleeding events. Consequently, there is renewed interest in the role of platelet PAR4 in the setting of thrombus formation. Objectives To determine the specific antiplatelet effects of inhibiting PAR4 function during thrombus formation in human whole blood. Methods and Results We developed a rabbit polyclonal antibody against the thrombin cleavage site of PAR4, and showed it to be a highly specific inhibitor of PAR4-mediated platelet function. This function-blocking anti-PAR4 antibody was used to probe for PAR4-dependent platelet functions in human isolated platelets in the absence and presence of concomitant PAR1 inhibition. The anti-PAR4 antibody alone was sufficient to abolish the sustained elevation of cytosolic calcium level and consequent phosphatidylserine exposure induced by thrombin, but did not significantly inhibit integrin αII b ß3 activation, α-granule secretion, or aggregation. In accord with these in vitro experiments on isolated platelets, selective inhibition of PAR4, but not of PAR1, impaired thrombin activity (fluorescence resonance energy transfer-based thrombin sensor) and fibrin formation (anti-fibrin antibody) in an ex vivo whole blood flow thrombosis assay. Conclusions These findings demonstrate that PAR4 is required for platelet procoagulant function during thrombus formation in human blood, and suggest PAR4 inhibition as a potential target for the prevention of arterial thrombosis.

Fate of the stented arterial duct.

BACKGROUND: The technical aspects of ductal stenting have been reported, but little is known of the fate of the duct after stent implantation. METHODS AND RESULTS: Nineteen patients underwent stent implantation to maintain ductal patency. Eight had hypoplastic left heart (HLH) syndrome, 10 had pulmonary atresia, and 1 had tricuspid atresia. Median survival with HLH was 57 (12 to 907) days. Stent implantation was successful in all cases of HLH, but there were no long-term survivors. Two well-palliated infants died at transplantation. Median survival with duct-dependent pulmonary flow was 183 (0 to 1687) days, with 3 patients well at latest follow-up (56, 55, and 9 months, respectively). There were 2 operative deaths due to ductal spasm and 4 late deaths, 1 due to duct thrombosis, 1 due to chronic lung disease, and 2 of unknown cause. Stent implantation failed in 4 of the 11 cases. Assessment of endothelialization was possible in 13 cases; the stent was partially covered in 3 and fully endothelialized in all 10 cases assessed >8 weeks after implantation. In patients stented for inadequate pulmonary flow, ductal intimal hyperplasia occurred by 9 months in all 3 survivors but responded to repeated dilation. CONCLUSIONS: Ductal stenting cannot be recommended. In patients with HLH, it provides only short-term palliation even when combined with pulmonary artery banding. With duct-dependent pulmonary blood flow, the procedure carries high risk, and duration of palliation is poor. In patients with bilateral ducts and absent central pulmonary arteries, good palliation may be achieved, but repeated angioplasty is necessary to counteract intimal hyperplasia.

Itraconazole therapy for cryptococcal meningitis and cryptococcosis.

We studied the efficacy of itraconazole, a new oral triazole, in 33 patients (32 were immunocompromised) with cryptococcosis. Diagnoses included cryptococcal meningitis (24 patients), cryptococcemia (19 patients), cryptococcuria (4 patients), osteomyelitis (1 patient), pulmonary cryptococcosis (1 patient), and soft-tissue cryptococcosis (2 patients). Twenty-six patients had the acquired immunodeficiency syndrome, and 4 were transplant recipients. Therapy (200 mg two times per day) was monitored by clinical response, culture, and cryptococcal antigen testing. Cryptococcemia was abolished in 10 (100%) of 10 assessable patients; clinical abnormalities also cleared. Thirteen (65%) of 20 assessable patients with cryptococcal meningitis had complete responses (clinical resolution and negative cultures), 5 (25%) had partial responses, and therapy failed in 2 (10%). Ten (71%) of 14 patients with the acquired immunodeficiency syndrome who had meningitis and were treated with itraconazole as their sole therapy had complete responses, 3 (21%) had partial responses, and therapy failed in 1 (7%). Partial responses or failures were all associated with the failure of previous therapy, severe disease, low serum itraconazole concentrations, or a resistant organism. Noncompliance was associated with relapse (4 patients). Meningitis recrudesced in 3 (20%) of 15 patients who responded to therapy. All 4 patients with pulmonary cryptococcosis, soft-tissue cryptococcosis, or osteomyelitis responded to therapy (100%). Cryptococcuria was abolished in 3 (60%) of 5 assessable patients. The median survival of the 20 patients with the acquired immunodeficiency syndrome who had meningitis exceeded 10.5 months at this writing. Overall results compare favorably with amphotericin B therapy with or without flucytosine. Forty of 44 isolates of Cryptococcus neoformans were susceptible in vitro to itraconazole (minimum inhibitory concentration less than or equal to 3.13 mg/L), 3 were borderline (minimum inhibitory concentration, 6.25 mg/L), and 1 was resistant (minimum inhibitory concentration, 12.5 mg/L). As itraconazole does not penetrate cerebrospinal fluid, the meningitis results are noteworthy and suggest that meningeal and parenchymal penetration is critical. Itraconazole is promising for the treatment of cryptococcosis in patients with and without the acquired immunodeficiency syndrome.

Prevalence of measles antibodies in adults with HIV infection: possible risk factors of measles seronegativity.

OBJECTIVES: To determine the prevalence of measles (rubeola) immunity in a group of HIV-1-infected adults and to examine predictors of measles seronegativity in this population. SETTING: County hospital outpatient clinic and public-health department early HIV intervention clinic. PATIENTS: A total of 262 HIV-infected adults presenting to outpatient clinics between September 1990 and January 1991. INTERVENTIONS: Patients were screened for the presence of measles immunoglobulin G antibody, as measured by an enzyme-linked immunosorbent assay (ELISA). Pertinent clinical and immunologic information was recorded. Univariate and multivariate analyses were performed to identify possible risk factors for measles seronegativity. MAIN OUTCOME MEASURE: Measles seronegativity, as defined by a lack of detectable antibody (ELISA predicted index value < 1.0). RESULTS: Thirteen (5%) patients lacked serologic evidence of immunity. Risk factors for measles seronegativity included year of birth in 1957 or later, Caucasian (non-Hispanic) race and oral hairy leukoplakia. Factors associated with progressive HIV disease (other than hairy leukoplakia) were not associated with a lack of existing immunity. CONCLUSIONS: A high prevalence (95%) of measles antibody was found in this large group of HIV-infected adults. Young, white individuals born in 1957 or later were at the greatest risk for measles seronegativity, but declining immunity due to progressive HIV infection did not appear to be associated with a lack of antibody. Self-reported histories of measles infection or immunization were not reliable predictors of measles immunity.

Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets.

Platelets from protease-activated receptor 4 (PAR4)-deficient mice are unresponsive to thrombin, and Par4-/- mice have prolonged bleeding times and are protected against thrombosis. However, in addition to its role in platelets, PAR4 contributes to thrombin signaling in cells in the blood vessel wall that might participate in hemostasis and thrombosis, such as endothelial cells. To determine whether the hemostatic and thrombotic phenotypes of Par4-/- mice were due to loss of PAR4 function in hematopoietic vs. other cell types, tail bleed times and thromboplastin-induced pulmonary embolism were examined in lethally irradiated mice reconstituted with Par4+/+ or Par4-/- bone marrow. In Par4+/+ and Par4-/- mice reconstituted with Par4+/+ marrow, the median tail bleed times were 2.0 and 1.7 min, respectively, vs. > 10 min for both Par4+/+ and Par4-/- mice reconstituted with Par4-/- marrow. In the pulmonary embolism model, Par4+/+ and Par4-/- mice reconstituted with Par4+/+ marrow survived a median of 3.7 and 2.8 min, respectively, after administration of thromboplastin, vs. > 20 min for both Par4+/+ and Par4-/- mice reconstituted with Par4-/- marrow. Further, the phenotype of mice reconstituted with Par4-/- marrow was almost as dramatic as that seen in Nf-e2-/- mice, which lack platelets. These data strongly suggest that increased tail bleed times and protection against thrombosis in Par4-/- mice are accounted for by lack of PAR4 function in platelets, emphasize the importance of thrombin signaling in platelets among the multiple pathways and cell types that govern hemostasis and thrombosis.

Donor organ transmission of varicella zoster due to cardiac transplantation.

BACKGROUND: We report a case of donor-transmitted varicella zoster viral (VZV) infection in a cardiac transplant recipient. A 15-month-old girl developed primary VZV infection 12 days after cardiac transplantation. The donor suffered from varicella 2 weeks before death from pneumococcal meningitis. METHODS: Despite treatment of the seronegative recipient with intravenous acyclovir from the time of surgery, she developed symptoms of fever, a nonspecific macular rash, and small palatal vesicles. RESULTS: After rapid diagnostic confirmation by direct immunofluorescence on vesicular fluid, high-dose intravenous acyclovir was commenced. In addition, the cyclosporine dose was reduced by 25%. The child made a quick and uncomplicated recovery. CONCLUSIONS: Donor organ transmission of VZV has not, to our knowledge, been previously reported. It occurred despite treatment with acyclovir and resulted in an atypical cutaneous eruption. It responded to an increased dose of acyclovir and a reduced level of immunosuppression.

High prevalence of anemia after cardiac transplantation in children.

BACKGROUND: Chronic anemia is common in adults after successful cardiac transplantation. However, the prevalence of anemia in children after cardiac transplantation is uncertain. The purpose of this study was to investigate the prevalence and causes of chronic anemia in well children after cardiac transplantation and in particular to define the role, if any, of iron deficiency, which is important and relatively common in normal children. METHODS: Twenty children (ages 7 months to 16 years) who were well 4 months to 6 years after cardiac transplantation were studied. Fourteen children (70%) were anemic and enrolled in a prospective trial of iron supplementation. RESULTS: In the majority of children, serum iron and erythropoietin levels were low, although serum ferritin and zinc protoporphyrin levels tended to be normal or high. Only one child demonstrated a definite response to iron supplementation, although the hemoglobin level remained low. CONCLUSIONS: Anemia is highly prevalent in this population, and, despite the presence of low serum iron and transferrin saturation, anemia is not usually due to iron deficiency. Although the diagnosis of iron deficiency in this group is difficult and must not be missed, inappropriate therapy should be avoided. In the majority of children, there appears to be an anemia of chronic disease which may be secondary to chronic inflammation or an effect of cyclosporine on erythropoietin production.

Posttransplantation B lymphoblastic leukemia with Burkitt-like features.

BACKGROUND: Posttransplantation Epstein-Barr virus-associated lymphoproliferative disease (PTLPD) occurs as a spectrum of disease ranging from benign, polyclonal, localized lymphoid hyperplasia to malignant, monoclonal, disseminated lymphoma, sometimes involving the bone marrow. To our knowledge, PTLPD has not been previously reported to present as acute lymphoblastic leukemia. METHODS: We report the case of a boy who developed PTLPD in the form of acute lymphoblastic leukemia 6 years after cardiac transplantation. He had greater than 90% bone marrow invasion by Epstein-Barr virus-positive B lymphoblasts with Burkitt-like features and a t(8;14) translocation. RESULTS: He was successfully treated with combination chemotherapy but unfortunately died, 6 months after completing treatment, from ischemic heart disease. CONCLUSIONS: B lymphoblastic leukemia may occur as a manifestation of PTLPD and should be included in the classification of these diseases. Bone marrow examination should be an essential part of the investigation of patients suspected of having PTLPD.

Diet and growth in congenital heart disease.

To assess the relationship between diet and growth in congenital heart disease we studied nutrient intake, body measurements, and cardiac status in 568 affected ambulatory patients less than 11 years of age. Most had mild heart disease, 104 were cyanotic, and only 10 were in congestive heart failure. Major disturbances of growth were uncommon. For the entire group body weight was below normal but only in those studied before 2 years of age; rate of growth and weight gain were normal over the period preceding the dietary study. There was no statistically significant relationship between intake of calories, protein, or other nutrients and growth or gain, analyzing the entire group, or analyzing patients subgrouped according to age, severity of heart disease, or severity of growth retardation. Body size and growth were diminished in cyanosed compared with noncyanosed children but cardiac status had no effect on nutrient intake. We conclude that in children with growth failure associated with congenital heart disease, nutrient intake is not an important factor limiting their growth.

Treatment failure in celiac disease due to coexistent exocrine pancreatic insufficiency.

A 17-year-old white adolescent had a history of chronic diarrhea, delayed puberty, and growth failure. Investigations excluded cystic fibrosis, Shwachman syndrome, and endocrine causes of growth failure. Severe steatorrhea was diagnosed from fecal fat studies, and a jejunal suction biopsy showed total villus atrophy, consistent with a diagnosis of celiac disease. Following introduction of a gluten-free diet, his appetite and growth improved, but he continued to have abdominal discomfort and loose offensive bowel motions. One year later, severe steatorrhea was present. A repeat jejunal biopsy showed partial recovery of villus architecture. Serum immuno-reactive trypsinogen level was low, which was highly suggestive of exocrine pancreatic failure. Results of quantitative pancreatic stimulation test confirmed the presence of primary pancreatic insufficiency. After introduction of oral pancreatic enzyme supplements with meals, his gastrointestinal symptoms resolved and growth velocity accelerated. Previously, primary pancreatic insufficiency has only been described in elderly patients with long-standing untreated celiac disease. This case, however, emphasizes that pancreatic failure can occur with celiac disease at any age. Determination of a serum immunoreactive trypsinogen level should be considered a useful screening tool for pancreatic insufficiency in patients with celiac disease who have not responded to a gluten-free diet.

Radionuclide angiography as the primary investigation in chemodectoma: concise communication.

A technique is described for investigating tumors of the carotid body and glomus jugulare. The examination comprises an easily performed radionuclide angiogram, and has been used to investigate 30 patients. This technique demonstrated seven carotid-body tumours, including two unsuspected clinically, and one tumor of the glomus jugulare. There was also one patient with a false-positive test for bilateral carotid-body tumors. Angiographic and/or surgical confirmation was obtained in all cases but one. A significant incidence of complication during contrast angiography was noted (two cases of transient hemiparesis). The radionuclide angiogram proved safer than contrast angiography and more reliable than clinical examination; it therefore appears to be the method of choice as the primary screening test in patients with suspected carotid-body and glomus-jugulare tumors.

Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery.

1. Mechanisms of protease-activated receptor-1 (PAR1)- and PAR2-induced relaxation were investigated in pre-contracted porcine coronary artery ring preparations. 2. Thrombin (0.01 - 0.3 u ml(-1)) and the PAR1-activating peptide SFLLRN (0.1 - 10 microM) caused concentration- and endothelium-dependent relaxation. pEC(50)s (-log u ml(-1) for enzymes, -log M for peptides) and maximum relaxations (R(max), %) for thrombin were 1.8+/-0.1 and 93.5+/-2.8% respectively, and for SFLLRN 6.8+/-0.1 and 90.8+/-1.3%. Similar concentration- and endothelium-dependent relaxations occurred with trypsin (pEC(50) 2.3+/-0.2; R(max) 94.1+/-1.9%) and the PAR2-activating peptide SLIGRL (pEC(50) 6.5+/-0.2; R(max) 92.4+/-1.6%). 3. Relaxations to thrombin, SFLLRN, trypsin and SLIGRL were significantly inhibited (P<0.05) to similar extents by the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM) and the NO scavenger oxyhaemoglobin (20 microM), both separately and in combination. 4. In the presence of the L-type voltage-operated calcium channel (L-VOCC) inhibitor nifedipine (0.3 microM), K(+) (67 mM) abolished the L-NOARG-resistant relaxations to thrombin, SFLLRN, trypsin and SLIGRL. However, nifedipine alone significantly (P<0.05) reduced the pEC(50) (1.5+/-0.1) and R(max) (77.5+/-7.0%) for thrombin but had no effect on relaxations to SFLLRN, trypsin or SLIGRL. Furthermore, L-NOARG-resistant relaxations to thrombin were abolished by nifedipine, whereas relaxations to SFLLRN, trypsin or SLIGRL were not further inhibited by combined treatment with nifedipine and L-NOARG, than they were with L-NOARG treatment alone. 5. Similar selective inhibition of the L-NOARG-resistant relaxation to thrombin, but not SFLLRN, occurred with verapamil (1 microM) and diltiazem (3 microM). 6. Our results suggest heterogeneous mechanisms in the NO-independent relaxation to thrombin and peptide activators of PAR1 in the porcine coronary artery.